Observations on some extra-adrenal effects of corticotropin on carbohydrate and lipid metabolism in man

Observations on Some Extra-Adrenal Effects of Corticotropin on Carbohydrate and Lipid Metabolism in Man B~J T. C. B. $rAhlP, J. LANDON AND V. W~~‘NK The possible significance of the reported extra-adrenal effects of corticotropin on lipid and carbohydrate metabolism has been studied in man. The fasting concentrations of blood sugar and pyruvate, and of plasma cholesterol and nonesterified fatty acids (NEFA) lay within normal limits in a group of patients with primary adrenal insufficiency, and the increase in nonesterified fatty acid levels during a 4 hour infusion of saline solution was significantly less than that observed in a group of control subjects. Since these patients might be expected to have elevated circulating levels of corticotropin it would appear that physiologic amounts of this hormone do not have significant extra-adrenal metabolic effects. In a group of patients with pri-

mary hypopituitarism and secondary adrenocortical insufficiency who might be presumed to have negligible levels of circulatory corticotropin, fasting conof blood sugar, plasma centrations NEFA and cholesterol were also normal. These values and the increase in NEFA levels during a 4 hour infusion of saline were similar to those found in the primary hypgadrenal group. In patients with primary adrenal insufficiency the intravenous infusion of pharmacologic amounts of corticotropin and of the synthetic polypeptide /31-24 corticotropin were also without significant effects on these indices, as compared with the control infusion of normal saline solution. (Metabolism 14: No. 10, October, 1041-1050, 1965)

W

HILE THE MAIN EFFECTS of corticotropin are to stimulate the rate of synthesis and release of adrenal steroids and to maintain the size of the adrenal cortex, there is now evidence, extensively reviewed by Engel.’ that corticotropin has several actions which are not mediated by the adrenal gland. Among these extra-adrenal effects Engel has listed certain actions 011 lipid and carbohydrate metabolism. Thus in some species corticotropin mav increase fat mobilization, produce ketosis and hypercholesterolemia, and induce hypoglycemia and improve glucose tolerance. The evidence for these extra-adrenal metabolic actions of ACTH has been based mainly on in vitro experiments and on animal studies and there is little information regarding their physiologic importance in man. We decided to investigate this problem in man by comparing fasting levels of blood sugar, pyruvate, lactate, plasma nonesterified fatty acids ( NEFA), and cholesterol in normal subjects with those found in patients with primary ___ --_-

From the Metabolic Unit, St. Mary’s Hospital, London, England. Received for publication July 7, 1965. TREVOR C. B. STAMP, M.B., B.CHIR., M.Sc. (Yale}: Assistant to the Metabolic Unit, Dept. of Human Metabolism, St. Mary’s Hospital, London, England. JOHN LANI>ON, M.D. (London): Lecturer in Chemical Pathology, Dept. of Hrlnlan Metabolism, St. Mary’s Hospital, London, England. VICTOR WYNN, M.D. (Mrlbournc): Reader in Human Metabolism, Dept. of Human Metabolism,

St. Mary’s Hospital,

London, 1041

England.

1042

STAMP,

Table I.-Clinical Secondary

LANDON AND WYNN

Data of Patients with Primary or Adrenal lnsuficiency &placement Thernrv

(mg./day) ~~_.____

~_ Case NO.

Sex

1. 2. 3.

F F F

46 49 32

4. 5. 6.

F F 1\1

7. 8.

Diagnosis

__

_~

..~__

Bilateral

adrenalectomy;

Gushing’s

syndrome

49 36 19

Bilateral Bilateral Bilateral Bilateral Bilateral

adrmalectomy; adrcnalectomy: adrmalectomy; adrenalectomy; adrrnalectomy;

Gushing’s Cnshing‘s Gushing’s Cl1shing.s Gushing’s

syndrome syndromcl syndrtune syndrome syndrome

hl A1

35 36

Addison’s disease Acromegaly; AII’Q~ pituitary

9. 10. 11. 1”. 13.

F F hl 11 hl

58 36 17 19 60

14. 15. 16. 17.

I\1 F F hI

56 30 36 24

Acromegaly; hypophyscctomy Chromophobe ndenoma; hypophysectom) Chromophobe adenoma; hypophyscctcm~y Craniopharyngioma; hypophyscx%omy Chromophohe adenoma Chromophohe adenoma Sheehan’s syndrome Acromegaly; Chromophohe

In addition to the replacement stcrone (5 mg. daily), ancl cases

implant

hypophysectamy adenomn; hypophyscctomy therapy listed, 10 and 11 were

case 13 was also rrceiving pitrcssin

I,I~‘luoroCortisol cortisol thyroxiw _____. 20 0.1 -

‘0 30

0.1 0.2

-

30 2.5 no 30 :30 “0

0.1 0.1 0.2 0.2 -

1 0.2 0.2

20 20

_ _

0.3 (L-7

30 1.5

-

0.3 0.1

20 Xl

-

0.2

“(1 “0

-

rccciving methyl tannatc in oil.

tcsto-

adrenal insufficiency, a condition known to be associated with elevated circnlating ACTH IeveIs,?J and in hypopituitary patients with negligible amounts of circulating ACTH as evidenced by the presence of secondary adrenal insufficiency. The effect of infusing pharmacologic amounts of ACTH on these levels wits also investigated. In order to exclude actions mediated by its steroidogenic effects these studies were confined to patients with no detectable adrenal function. To avoid effects caused hy other pituitary hormones only highly purified corticotropin was used and additional studies were performed cm ploying a pure synthetic tetracosapeptide ,B-z-Lcorticotropin. This polypeptide is identical in structure with the N-terminal 24 amino-acids of the natural hormone, and has equivalent steroidogenic activity.4 MATEKIAL

AND METHODS

Subjects Seventeen patients with clinical and biochemical evidence of primary or secondar! adrenocortical insufficiency were studied. Particulars of their age. sex. diagnosis and replacement therapy are given in table 1. Control data were obtained from patients matchecl for age and sex who had no evidence of endocrine. renal or hepatic malfunction. The 15 control subjects studied during a 4 hour prolongation of the period of fasting also included 7 male medical students aged 22 to 25. Their clata did not differ significantly from that of the control patients.

Procedures Blood samples which replacement

were taken between 9 and 10 am. after a 12 to 14 hour fast during therapy was withheld. Tests were performed lmcler the same conditions

EXTRA-ADRENAL

EFFECTS

Table 2.-Fasting Metabolism

1043

OF ACTH

Levels of Various lndicea of Carbohydrate and Lipid in Control Subjects and in Patients with Primary or Secondary Adrenal Insufficiency Seven Patients with Primary Adrenal Insufficiency

Control Subjects

Blood

Ten Patients with Secondary Adrenal insufficiency

sugar

(mg./lOO ml.1 Blood pyrnvatt (mg./lOO ml.) Plasma cortisol

(~g./lOO ml. ) Plasma cholesterol (mg./lOO ml.) Plasma NEFA

76-c

81 -c 13* (4o)t (1.48 -c 0.09 (40) 12.8 I 195 t

t

73 +_ 6

0.10

0.52 t

0.08

3.1 (100)

4.3 & 1.8

4.0 i

1.2

( 30)

w-3 i 41

202 i Wf

32

0.48

12

575 i 160 (50 ) 300 2 1% 530 * _.__.. ~~~ _ ~~~. _._ .~~ ~~ ._~~~ ~ ~~~ ‘Mean -C standard deviation. +The figures in parentheses refer to the number of control sltbjtbcts studied. (pEq./L.)

$This thyroxine

value does not include 2 patients and who were subscq~l~~ntlp found

I10

(cases 16 and 17) who wcrr not rrcciving to have secondary hypothyroidism.

I,-

using nn indwelling

Frnnkis-Evans needle inserted into a forearm vein. Each of the patients with primary adrenal insl&iency (cases l-7) were studied during a 5 hour infusion of highly purified porcine corticotropin ( Organon ) dissolved in isotonic saline and infused at a rate of 10 i.u./hour. In addition. 3 of these patients were stltdied during the infusion The tetracosaof isotonic saline alone, and 4 dlrring the infllsion of /31-s-l corticotropin. which is eqllivalcnt on an adrenal peptide was administered at a rate of 100 bLg./hoor, stimulating basis to the infusion of 10 i.ll./hollr of thr natural hormone.4 Blood sugar levels were determinc~tl by the Hoffman ferricyanide method, modified cholesterol by a modification of the mcthnd of Zlatkis, Zak ,ISC with an autoanalyser,” Boyle.‘J NEFA by the single extraction fluarimetric method.” Specific enzyme pyruvaten and lactate.10

method methods

fol ant1

of Dole and 7vleinertz.i and cortisol by a were llsecl for the tlrtrrminntinn of blood

RESULTS

From 2-5 daily detenninations of the circulating levels of sugar, pyruvatc. cholesterol. NEFA, and cortisol were performed in the patients with primarv or secondary adrenal insufficiency. The mean results for these 2 groups arc compared in table 2, with the values found in control subjects. The mean resting plasma cortisol concentration of 4.3 /lg./100 ml. found in patients with primary adrenal insufficiency was similar to the value of 4.0 ,~g./lO0 ml. found in the patients with hypopituitarism and secondary adrenal insufficiency. These levels represent the cortisol still circulating following the maintenance dose of steroid given the previous evening. The mean blood sugar, pyruvate, cholesterol and NEFA concentrations were also similar in the 2 groups of patients and the individual results all lay within the normal range with the exception of 2 patients (cases 16 and 17) with hypopituitarism WOO had abnormally elevated plasma cholesterol values (400 and 293 mg./lOO ml., respectively ) . These 2 patients, who were not receiving L-thyroxine, were’ subsequently shown to have secondary hypothyroidism. NEFA levels were followed during a 4-hour prolongation of the period of fasting in 4 patients with primary adrenal insufficiency and in 4 patients with

1044

STAMP,

Table 3.-Plasma Overnight

Case Case Case Case

no. 1 no 2 no. 5 no. 7

Mean change

Plasma NEFA. #Eq./L. of Prolongation of the Normal Overnight Fast (mins.)

60

120

506

568

693

-

tFi2

-t 187

- 539

-

50

134

118

0

SD. of mean changr

AND WYNN

NEFA Levels during a I-Hour Prolongation of the Normal Fast in Control Subjects and in Patients with Primary or Secondary Adrenul Znsuficiency Duration

Mean levels in 15 control subjects Mean change in 15 control subjects

LANDON

180

806

Patients 2&h primary hypoadrrnnlknl 44.5 457 395 576 5133 449 443 364 312 684 628 576 -

$55

240

+300

178

378 517 43s (i:30 +,x3

f105

Patients with secondary lfy~Jr~arlrenali.sr,i Case Case Case Case

no. no. no. no.

8 14 15 16

Mean change

562 476 820 413 -

635 479 855 366 f16

447 578 802 390 -14

641 550 801 403 +33

614 605 820 447 +53

hypopituitarism. The individual values are given in table 3, together with the mean levels obtained in a group of 15 control subjects. There was no statistical difference between the 2 hypoadrenal groups, except possibly at 2 hours (0.05 > p > 0.02). Both these groups, however, showed a significantly impaired plasma NEFA rise compared with control subjects (difference between controls and hypopituitary subjects 0.01 < p < 0.02 both at 3 and 4 hours. and between primary hypoadrenal subjects and control subjects 0.01 < 1~ < 0.02 at 3 hours and 0.05 > p > 0.02 at 4 hours). The response of the circulating levels of cortisol, sugar, pyruvate, Inctatc. cholesterol and NEFA to the intravenous infusion of corticotropin (10 i.u./ hour ) or /31mz4 corticotropin (100 pg./hour) was studied in subjects with primary adrenal insufficiency, Plasma cortisol levels determined prior to, and at the end of a 5 hour infusion of ACTH did not increase notably in any patient, the mean concentrations being 4.3 and 3.9 p,g./lOO ml., respectively. The mean circulating levels of sugar, pyruvate, lactate, cholesterol and NEFA determined in the 7 patients during the infusion of porcine ACTH are shown in figure 1, together with the mean values obtained in 4 of these patients during the infusion of ,Gzr corticotropin, and in 4 during the control infusion of isotonic saline. During the 5 hour infusion of saline the mean blood sugar fell by 4 mg./ 100 ml., the mean blood pyruvate by 0.21 mg./lOO ml., and the mean blood lactate by 1.2 mg./lOO ml. Similar slight decreases were also observed during the infusion of ACTH and of the synthetic polypeptide.

STHA-ADRENAL

1045

EFFECTS OF ACTII

Blocd

Jo&v

! rn~/loornl

I

z-s 70:---------Q_______;__

f

_____-----

3

I

PlOsmo choleskrol(mp/lOOml~ 240 230

Fig. l-The effect of infusing and fil-24 corticotropin (0 -----0) sugar, pyruvate, lactate. cholesterol aclrenalism.

corticotropin saline ( l -‘), porcine [ 0 - - - - - - - 0) on the circulating levels of and

NEFA

in patients

with

primary

hype-

The plasma cholesterol concentration remained virtually unchanged throughout the control infusion and was not significantly affected by either the natural hormone or the tetracosapeptide. The mean NEFA increases of 110 and 119 pEq./L. which occurred during the infusions of corticotropin and of /?-zr corticotropin were similar to the increment of 92 /IEq./L. observed during the infusion of isotonic saline. NEFA concentrations were also determined in 2 of the totally adrenalectomized subjects during a 3 hour infusion of ACTH (10 i.u./hour) with and without the prior intravenous administration of cortisol ( 1 mg./Kg. body wt. ) for comparison with the results obtained during the infusion of saline. Values

1046

STAMP,

LANDoh‘

AND WYSS

Table 4.-Plasma NEFA Changes in 2 Totally Adrenalectomized Subjects the Znfusion of Saline, of Corticotropin and of Corticotropin after the Intravenous Administration of Cortisol .______ PlasmaNEFA (sEq./L.) Ihration

Ii0

130

1 -7 1

457 503 37”

445 576 472

561

683

66”

861

506

,568

69.3

74.5

Corticotropin infusion without prior cortisol loading Corticotropin infusion following i.v. administration of cortisol (1 n~g./Kg. body wt.) Saline infusion in 15 control subjects are given

4 and show that

in table which

followed

double

those observed

closely

matched

of Infusinn (min.)

Subject

Saline infusion

,lEq./L.

during

the

the maximal

administration

during the infusion

-.

were

of saline or ACTH

the value of 239 pEq./L.

found

304 and 300

of

increments

of cortisol

approximately alone,

in the group

and more

of control

sub

jects. DISCUSSION

reported that relatively pure corticoIn 1953 Astwood and his co-workers’l tropin produced ketonuria and an increase in hepatic fat content in cortisoncmaintained

adrenalectomized

determining

NEFA’” and the subsequent realization of their physiologic imseveral studies concerning the effects of corticotropin on NEFA

portance,l” levels

have

been

made.

incubation

of rat adipose

centration

of NEFA

Similar

results

pituitary

have

peptides

mice.

Thus

With

the advent

it was first shown

tissue with ACTH

of reliable

by White

methods

and Engel,‘-L

in vitro greatly

increased

both in the tissue and in an albumin-containing been

reported

together

by several

with epinephrine

groupsrn-li

that

the conmedium.

and although

and norepinephrine

for

oth(br

cause similar

effects, ACTH is the most potent, 0.01 pg./ml. rR This lipolytic action

regularly acting at concentrations of about of corticotropin is in part due to the direct

activation

than

reflect

of a tissue

the inhibitory

lipase action

other

lipoprotein

of corticotropin

lipase,l!’

on triglyceride

and mav in part synthesis.“”

Thea

elects are also shared by synthetic polypeptides such as the tetracosapeptidc /3’-“-‘-corticotropirri and the decapeptide /11-10-corticotropin,21 which consist of part of the N-terminal sequence of the natural hormone. Even peptides lacking the N-terminal serine of ACTH which are without steroidogenic activity mnv increase NEFA release from adipose tissue in vitro.“’ An accelerated

NEFA

ficult to demonstrate

rise during

in vivo. Thus,

ACTH although

administration found

is much

in the rabbit’”

more

dif-

and rat.”

the injection of ACTH has relatively little effect on plasma NEFA levels in the dog or man.23-‘Jj In the intact animal it is possible that the effects of an increase in circulating steroids may mask any extra-adrenal effects of cortico-

EXTRA-ADRENAL

EFFECTS

OF ACTH

1047

tropin. Thus Ho and Meng”’ reported that ACTH did not increase NEFA levels in fasting intact rats but did in eviscerated adrenalectomized rats, while Gordon?’ reported a marked increase in the circulating levels of cholesterol and NEFA when patients with primary adrenal insufficiency were infused with corticotropin. In the present study, it was not possible to demonstrate any extra-adrenal effect of endogenous ACTH on lipid metabolism. Thus the mean resting plasma cholesterol and NEFA concentrations were similar in a group of patients with primary adrenal insufficiency (and presumed high levels of circulating ACTH) to those found in a group of patients with secondary adrenal insufficiency and negligible circulating ACTH levels due to hypopituitarism. The NEFA increment found during a 4-hour prolongation of the period of fasting was also similar in these 2 groups and was significantly less than that observed in control subjects. An impaired NEFA response to fasting has also been reported by others in adrenalectomized animals,” and in hypopituitary patients.“!’ Other studies support the view that increased levels of endogenous ACTH do not cause significant extra-adrenal lipid effects; thus there is no significant difference between the energy expenditure, food intake and carcass and hepatic lipid content of adrenalectomized mice and of adrenalectomized mice with corticotropin producing tumors,“” and no significant increase in NEFA values in control subjects injected with the corticotropin-releasing compound lysine vasopressin.“’ The results obtained during the infusion of corticotropin and of ,Q1-2* corticotropin in pharmacologic amounts, some 30 times greater than those required to cause maximum adrena stimulation, R2to patients with no detectable adnxnal function would appear to indicate that even high concentrations of exogenous hormone are without significant extra-adrenal lipid effects. Thus there was virtually no change in plasma cholesterol values and the increase in plasma NEFA concentrations during the infusions was similar to the increment observed during the control infusion of saline. The maximum rise of NEFA values was also significantly lower than the increase found in a group of control subjects infused with saline. These results are not in agreement with those reported by Gordon,” but as he gave no detailed data. we are unable to offer an explanation for this discrepancy. In in vitro studies ACTH, in contrast to glucocorticoids, has been shown to stimulate the uptake of glucose by adipose tissu@ and to increase its rate of oxidation.:iJ This appears to be related to the increase in the concentration of NEFA within the tissue.“” It is associated with an increase in the size of the lactate po01,“~ consequent upon an increase in the rate of glycolysis by the Embden-Meyerhof pathway, and is also associated with a decreased rate of triglyceride synthesis from isotopically labeled pyruvate.2” Corticotropin has also been found to affect carbohydrate metabolism in some animals in vi1.o. Thus Westermeyer and Raben”” reported that its administration was associated with a fall in the blood sugar in adrenalectomized mice, and it has also been shown to lower the blood sugar and increase tolerance to intravenously injected glucose in adrenalectomized rats.“’ Thr results obtained in the present study suggest that increased levels of

1048

STAMP,

LAXDON

AND

WYNN

endogenous or exogenous corticotropin are not associated with marked extraadrenal effects on carbohydrate metabolism in man. Thus the fasting levels of blood sugar and pyruvate in patients with primary adrenocortical insufficiency were similar to those observed in patients with hypopituitarism and in control subjects. Similarly the infusion of corticotropin or of /.?-24 corticotropin in pharmacologic amounts to patients with no detectable adrenocortical function caused no significant change in the levels of blood sugar, pyruvatc or lactate as compared with the control infusion of saline. The present findings suggest that metabolic extra-adrenal actions of corticotropin may be without physiologic or pharmacologic importance in man. Scvera1 criticisms can, however, be leveled at the present investigation. In particular more dynamic studies such as the effect of corticotropin on the rate of utilization of isotopically labeled metabolites are required before such actions can be excluded. It is possible that the levels of circulating glucocorticoids present in the subjects investigated were inadequate since the lipolytic actions of corticotropin are dependent upon the presence of permissive amounts of these steroids.“8 It was found, however, that pretherapy with pharmacologic amounts of cortisol only resulted in a return to normal of the increase in NEFA levels during a 3 hour infusion of ACTH as compared with control subjects infused with saline solution. Moreover, the administration of cortisol alone to intact normal subjects, which is known to suppress the release of endogenous ACTH, is associated with a significantly increased rise of plasma NEFA levels above control values during an extended fasting period.“” ACKNOWLEDGMENT One

of us (T.

Research Council.

C.

B. S.) gratefully acknowledges financial assistance

from

the

Medical

REFERENCES 1. Engel, F. L.: Extra-adrenal actions ofadrenocorticotropin.Vitamins & Hormones 19:189, 1961. 2. Betlmnr, J. E., Nelson, D. H., and Thorn, G. W.: Plasma adrenocorticotrophic hormones in Addison’s disease and its modification by the a& ministration of adrenal steroids. J. Clin. Invest. 36:1701, 1957. 3. Nelson, D. H., hleakin, J. W., and G. IV.: ACTH-producing Thorn, pituitary tumours following adrenalectomy for Gushing’s syndrome Ann. Int. Med. 59:560, 1960. 4. Schuler, V. W., SchPr, B., and Depharmakologie saulles. P.: Zue eines ACTH-wirksamen vollsythetis&en polypeptids, des*-24 corticotropin. Ciba 30920 Ba. Synacthen. Schweizmed. Wschr. 93:1027, 1963. 5. Hoffman, W. S.: Rapid photoelectric method for determination of glucose

in blood and 120:51, 1937.

urine.

J,

Biol.

Chvln.

6. Zlatkis, A., Z.lk, B., and Boyl~, A. J.: A new method for thp tlil-cct tlctt,rminntion of scyrmn cholesterol. J. Lab. & Clin. Yled. .41:486, 1953. 7. Dolr, \‘. P., and .\leinertz. H.: hlicr-odetermination of long-chain fatty acids in plasma and tissncs. J. Biol. Chem. 23532595, 1960. 8. hlattingly, D. A.: A simple fluorimetric method for tllc estimation of frt~, 1 lhydrorycorticoitls in human plas~~~a. J. Clin. P,lth. 15:374, 1962. 9. Landon, J.. Fawcctt. J. K., and \1’ynn. V.: Blood pyruvate concentratiorl measured by a specific method in control subjects. J. Clin. Path. 15: 579, 1962. 10. Hess, B.: Ubpr zinc kinctisch-uwymatischc Restimmnng &r-L ( + )Milchsaure im menschlichen serum

EXTRA-ADRENAL

1049

EFFECTS OF ACTH

uncl anderen biologischen keiten. Biochem Z. 328:110,

Flussig1956.

11. Astwood, E. B., Raben, M. S., Rosenberg, I. N., and Westrrmeyer. V. W.: hletabolic effects of a pituitary extract. Scivncc 118:567, 1953. 12. l)ole, V. I’.: A relation bctrvecn nonrstcrified fatty acids in plasma and the metabolism of glucose. J. Clin. Invest. 35: 150, 1956. 13. I’redcrickson, D. S., and Gordon, R. S.: Transport of fatty acids. Physiol. Rev. 38:SSS. 1958. L-l. \Vhite, J. E.. and Engel, F. L.: Lipolytic action of corticotropin on rat adipose tissue in vitro. J. Clin. Invest. :37:1556, 1958. 15. Buckle,. R. 51.: The stimulating effects of adrenaline and anterior pituitary hormones on the release of free fatty acids from adipose tissue. J. Endocrinol. 25: 189, 1962. 16. Rudman, I>., Brown, S. J., and hlalkin, \I. I;.: Adipokinetic effects of ~ltlrc,rrocorticotropin, thyroid-stimulating hormone, vasopressin, 01 and p stimlllating hormones. melanocytcand norrpinephrinr in cpinq~hrincs the pig

2.3.

24. 25.

1958. Ho. R. J., and Meng, H. C.: TIw extra-cortical action of ad’renocorticotrophic hormone on the elevation of plasma free fatty acids. hletaholism 13:361, 1964. 27. Gordon, E. S.: In discussion. Amer. J. Clin. Nutrition 8:704, 1960. 28. Goodman. H. hl., and Knobil, E.: Effect of adrenergic blocking agents 26.

rabbit, gllinea pig, hamster. rat, and dog. Endocrinology 72:527,

1963. 17. Vaughan,

hl.,

Steinberg,

D.,

and

Shaf-

rir, E.: The effect of epinephrine, glucagon Ll adrcnocorticotropic hormone ( ACTH) on phosphorylase activity in adipose tisnc. J. Clin. Invest. 38: 1051, 1959. 18. Engel, F. L., and White, J. E.: Some hormonal influences on fat mobilization from adipose tissue. Amer. J. Clin. Nutrition 8:691, 1960. 19. Hollenberg, C. H., Rnben, M. S., and

20.

22.

Astwood, E. B.: The lipolytic response to corticotropin. Endocrinology 68589, 1961. Steinberg, D., Vaughan, M., and Mnr-

S.: Control of fatty acid readipose tissue through from control of rate of triglyceride synthesis. J. Biol. Chrm. 235:PC 38, 1960. 21. Tanaka, ,4., Pickering, B. T.. and Li, C. H.: Relationship of chemical structures to in vitro lipolytic activity of pcptides occurring in acl-

renocorticotropic melanocyteand stimlllating hormones. Arch. Biocllem. 99294, 1962. Girolamo, hl. D., Rudman, D., Reid, F.: Effect of hl. B., and Seidman, pituitary hormones upon serum frrc fatty acid concentration of the rabbit. Endocrinology 68:457. 1961. Raben, hl. S., and Hollenberg, C. H.: Etfect ot growth hormone on plasma fatty acids. J. Clin. Invest. 38: 484, 1959. -: Human growth hormone. Kecent Prog. in Hormone Res. 15:71. 1959. Laurcll, S., and Christensson, B.: Effect of a single dose of some hormones on plasma un-ester&d fatty acids Acta Physiol. Stand. 44:248,

on fatty acids during fasting. Proc. Sot. Esp. Biol. & Med. 102:493, 29.

30.

1959. Perry, \V. F., and Gemmel, J. P.: Plasma nonesterified fatty acids in hypopituitary Metabolism subjects. 9:501, 1960. hlayer, J., Zomzely, C., and Furth, J.: Body composition and energetics in obesity induced in mice by adrcnotumours. Science 123: 184, tropic

1956. 31. Lihrick, L.. and Clayton, G. IV.: The measurement of plasma nonesteritied fatty acid levels following ACTH release in man. hletabolism 12:790, 32.

golis,

lcase

33.

1963. Landon. J., James, V. H. T., Cryer, H. J., Wynn, V., and Frankland, A. W.: Tltc adrenocorticotropic ctfects of a synthetic polypepticleman. J. Clin. P1-= corticotropin-in Endocrinol. 24:1206, 1964. b’ain, J. N., Scow, R. O., and Chernick, S. S.: Effects of glucorticoids on metabolism of adipose tissue m vitro. J. Biol. Chem. 238:54, 1963.

1050

STAMP, LANDON AND WYNN

34. Lynn, W. S., Macleod, R M., and Brown, R. H.: Effects ok epinephrine, insulin and corticotropin on the metabolism of rat adipose tissue. J. Biol. Chem. 235:1904, 1960. 35. Leboeuf, B., and Cahill, G. F., Jr.: Studies on rat adipose tissue in vitro. VIII. Effect of preparations of pituitary adrenocorticotropin and growth 236:41, hormones. J. Biol. Chem. 1961. 36. Westermeyer, V. W., and Raben, M. S.: Fall in blood sugar from anterior pituitary extract. Endocrinology 54: 173, 37. Engel,

1954. M. G.,

and

Engel,

F.

L.:

In-

fluence fatty the 38. Li,

of acid

rat. I.,

G. F.,

Lost&, H. I).,

Sideman, X. 39.

Nayak, Carter,

P., T.,

Geschwind.

A. L., Lyons,

R.

V.,

J.

Esp.

B.,

and

1957. Feldman, cortisol

jects.

Sot.

1962.

R..

(ACTH).

E.

A. C.: Adipokinctic Proc.

W.

W. I>., and

investigations.

105:335,

in 1956.

Hungerford,

Reinhardt,

intravenous 3~682,

58:808,

ICI.: Corticotropins

Biological

Med.

metabolism

Fonss-Beth, Hayashida,

Moon,

,111

corticotropin

glucose

Endocrinology

C. H., I.

osycel and

Exp.

in

efkt human

Biol.

of sub-

& 11~1.